Mathis was born and raised in Marianna, Florida,[1] the son of Danny and Bunnee Mathis.[2] He has one brother, Jake, who played in the Minor Leagues.[3]

At Marianna High School, he played both football and baseball, winning four district titles, a regional title, and appearing in the state championship game in football in 2000, as well as a 1999 state title in baseball, on a team that featured fellow first-round pick Alan Horne.

He was a first round draft selection by the Angels out of high school in 2001, which he accepted in lieu of attending Florida State University.[1] He moved up the ranks to Triple-ASalt Lake by 2005. He earned the Angels' minor league Defensive Player of the Year award. Noted for his defensive skills at the catcher spot, he also had a career-best year with the bat, hitting .276 with 21 home runs.

Following the 2005 season, the Angels declined to pursue the return of their free agent starting catcher, Bengie Molina, ensuring Mathis would make the roster for the 2006 season.[4]

After a solid 2006 spring training, Mathis was expected to see substantial playing time at catcher, sharing the position with José Molina. However, once the regular season began, he struggled greatly on both defense and offense. With Mathis batting only .108 and the team compiling just a 2–9 record in games that he started, the Angels demoted him back to the minor leagues one month into the season. Mathis was replaced on the Angels roster by catcher Mike Napoli.

In 2008, he batted just .194, below the Mendoza Line. Mathis hit an 11th-inning walk-off RBI double in game three of the American League Championship Series defeated the New York Yankees 5–4.[citation needed]

His impressive 2009 playoff offensive statistics became important in his 2010 arbitration hearings. In spite of poor regular season stats (.211 average), he used his strong playoff offensive performance and excellent defensive skill to bolster his case for a raise to $1.3 million, beating the Angels management in arbitration.[5] The arbitration hearing was also something of a watershed in the amount of consideration paid to Mathis' defensive statistics. The LA Times highlighted the stark comparisons with competing catcher Mike Napoli: "in 657 innings with the agile Mathis behind the plate, Angels pitchers had a 3.99 earned-run average; they had a 4.86 ERA in 758 innings with Napoli catching. Mathis also caught 17 of 69 attempted base-stealers for a 24.6% success rate; Napoli, who will make $3.6 million in 2010 but is coming off two 20-homer seasons, caught 13 of 87 attempted base-stealers for a 14.9% success rate".[5] Mathis had been among the AL leaders in pitchers' earned run averages while behind the plate.[6]

In 2010, Mathis was ranked by Beyond the Box Score as one of the worst defensive catchers in baseball.[7] He also matched his career-worst batting average of .194, while posting a sub-.500 OPS in over 200 at bats.

Nine days later, Mathis signed a contract with the Blue Jays to avoid arbitration. He signed a one-year deal and was guaranteed to earn $1.5 million.[9] Mathis made his first career pitching appearance in a game against the Texas Rangers on May 25. Pitching in the 8th inning, Mathis gave up a hit and walked a batter, but ended the inning without surrendering a run. He became the sixth position player for the Blue Jays to pitch in a game, and the first since Mike McCoy on June 11, 2011.[10] He made a second pitching appearance exactly two months later, mopping up in a 16-0 loss against Oakland. In that game, Mathis gave up 3 hits and 2 runs (both earned) in 1 inning of work.

On August 14, 2012, Mathis was signed to a two-year contract extension worth $3 million. It included a 2015 club option worth $1.5 million. Mathis was hitting .215 with 6 home runs over 147 plate appearances at the time of extension.[11]

In his first spring training game with the Marlins on February 23, 2013, Mathis broke his collarbone on a foul tip hit by Matt Holliday. He was the only catcher with major-league experience besides Brantly, and was expected to miss 6 weeks.[13] Mathis made his season debut on May 16, going 0–4 with 2 strikeouts. On June 30, he hit a walk-off grand slam against Tyson Ross of the San Diego Padres to give Miami the win, 6–2.[3] On November 1, 2014, the Marlins exercised their $1.5 million 2015 option on Mathis.[14]

On December 18, 2015, Mathis re-signed with the Marlins on a 1-year deal worth $1.5 million.[15] He hit his third career grand slam (first since 2013) in a June 14, 2016 game against the San Diego Padres.[16]